1. Field of the Invention
The invention relates to controlled release systems, and in particular to double emulsion carriers containing alkaline compound.
2. Description of the Related Art
The desirability of coating medical devices such as, inter alia, surgical implants, sutures and wound dressings with pharmaceutical agents is well known. Such coated devices provide a means for locally delivering pharmaceutical or therapeutic agents at the site of medical intervention to treat a variety of diseases. For example, surgical implants or sutures coated with antibiotics can provide local delivery of antibiotic directly to an implantation or suture site, thereby decreasing the onset of infection following the surgical intervention.
Thus, there is an increasing interest in developing a drug delivery system which is both safe and which provides a high biological availability of the drug, i.e. to maximize pharmaceutical activity of known drugs as well as to minimize the side effects thereof. Due to their uniform release rate during a given time period and the non-toxic property of degradation products, biodegradable polymers have been widely investigated as drug carriers. Biodegradable polymer drug carriers are especially useful for delivering drugs requiring continuous and sustained release with a single bolus administration, e.g. peptide or protein drugs, which should be administered daily because of quick loss of activity in the body.
Aliphatic polyesters, such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), copolymers of PLA and PGA (PLGA) or poly(carprolactone) (PCL), and polyanhydrides have been widely used for biodegradable polymers. They can be formulated as various shapes, such as films, strips, fibers, gels or microspheres, and the physiologically active agents are incorporated into the formulations and administered intramuscularly or subcutaneously. However, microspheres have been a particularly preferred formulation because the drug release rate can be easily controlled and the small microsphere particle sizes of 1˜500 μm enables direct injection into the body by conventional methods. Preparation methods, however, to achieve uniform particle size of the microspheres and effective loading of drugs are still under investigation.
Microspheres have been prepared by various methods such as emulsion solvent evaporation, phase separation, spray-drying, or solvent extraction. However, improved methods for preparing microspheres having uniform particle size and effective drug loading are desirable. According to the emulsion solvent evaporation method, a hydrophobic polymer is dissolved in a water-immiscible organic solvent, such as dichloromethane, chloroform, or ethyl acetate, to give a polymer solution. Then, a physiologically active agent is dissolved or suspended in the polymer solution. The resulting solution is added into an aqueous solution of a surfactant to form an emulsion system, and microspheres are obtained by evaporating the solvent under vacuum or heating. Although this method is useful for very poorly water-soluble drugs it has very low loading efficiency for water-soluble drugs.
Ogawa et al. (Chem. Pharm. Bull., 1988: 36: p 1095-1103) disclose a w/o/w double emulsion method for incorporating a water-soluble drug into microspheres. Accordingly, a biodegradable polymer is dissolved in a water-immiscible organic solvent to give a polymer solution, and a water-soluble physiologically active agent is emulsified into the polymer solution to give a w/o emulsion system. This emulsion is emulsified again into an aqueous solution of a surfactant to produce the w/o/w double emulsion system. The microspheres containing the water-soluble physiologically active agent are obtained by evaporating the solvent. This method requires use of gelatin to increase the viscosity of the w/o emulsion and the loading efficiency decreases remarkably because the particle size of the microsphere is less than 10 .mu.m.
Additionally, a solid/oil/water (s/o/w) double emulsion method has been developed. In this method, proteins or drugs are freeze-dried to form a solid material, and encapsulated to a solid/oil/water (s/o/w) form. However, the protein drug without protection easily loses activity because the protein drug exists in an organic solvent by the solid form and proceeded with a freeze-dried procession. In addition, the solid-form complex is difficult to disperse into the first emulsion.
Thus, there is no currently available method or composition that can carry and protect sensitive drugs, specifically water-soluble drugs such as peptide, protein and nucleic acid. Furthermore, the hydrolysis of biodegradable material may decrease the pH of the biological subject, thus adversely affecting cell growth. To overcome the above problems, a controlled release system having a stable pH, effective carriage and protection of sensitive drug and a slow release rate is needed.